Rituximab, a monoclonal antibody targeting the CD20 molecule, has been extensively studied in patients with CD20-expressing malignancies. Although the majority of B cell-derived NHLs express the CD20 antigen only about 50% of the patients with relapsed B cell malignancies will respond to single agent rituximab. This suggest that there are mechanisms of resistance that need to be overcomed to obtain a higher rate of response that may translate into both longer disease-free survival and overall survival. We have been developing new combinations regimens, not involving chemotherapy, and determining their efficacy. In this context we have investigated the anti lymphoma activity of bryostatin-1 in combination with rituximab. The preliminary data suggest the following: 1) Bryostatin-1 and rituximab have direct and additive antitumor effects against NHL cell lines; 2) Bryostatin-1 enhances the expression of CD20 on NHL cells; 3) Bryostatin-1 enhances the expression ooof FCRIII on effector cells; 4) Bryostatin-1 decreases the expression of the complement inhibitory molecule CD59 ojn tumor cells; and 5) Bryostatin-1 decreases AKT phosphorylation on B cell lines. We hypothesize that bryostatin-1 through the above mentioned may increased the antitumor activity of rituximab without the toxicities associated with chemotherapy. Therefore, as a necessary step toward the development of effective immune strategies and to test out hypothesis we have designed a clinical trial in patients with rituximab refractory NHL or rituximab refractory CLL that will address the following key issues: I- Determine the feasibility and safety of administering bryostatin-1 and rituximab in the above-mentioned population; II- Evaluate the antitumor response in patients treated with the combination of bryostatin-1 and rituximab; III- Investigate the functional and molecular status of effector cells (NK cells, monocytes, and DC) as well as the expression of CD20 and complement inhibitory molecules on tumor cells; and IV- Analyze the phenotype of T helper cells and the global gene expression in tumor cells before and after treatment.